Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 83
Histone deacetylase inhibitor LAQ824 downregulates beta-catenin, inhibits cell
proliferation and induces apoptosis in colon carcinoma cell lines.
Ignacio Portero-Robles, Martine Pape, Sina Droll, Dieter Holzer, Ulrich Böcker, Martin
Ruthard, Oliver G. Ottman and Noriko Koyama.
Universitäts-Klinikum Frankfurt. ZIM II Hämatologie. Theodor-Stern-Kai 7 60590
Frankfurt am Main. Germany. E-Mail: robles@em.uni-frankfurt.de
Histone deacetylase (HDAC) inhibitors represent a class of anticancer agents that act by
promoting acetylation of histones, activating genes implicated in proliferation and apoptosis.
Mutations in the Wnt signaling pathway result in a continuous translocation of beta-catenin to
the nucleus acting as cofactor of TCF/LEF. Targets genes of these complex are constitutively
expressed inhibiting apoptosis and promoting tumor cells proliferation.
The aim of this study is to analyze the effect of LAQ824 (Novartis, Basel), a HDAC inhibitor,
in colon carcinoma cell lines and the contribution of the Wnt-signaling pathway to HDAC
inhibitor-induced apoptosis and inhibition of cellular proliferation.
After treatment with 10 to 200nM of LAQ824, we show acetylation of histones -3 and -4 and
induction of p21Waf/Cip1. Under the same condition cell proliferation is inhibited, annexin-V
expressing cells are increased, caspase -3, -9, -8, -2 as well as PARP cleavage is observed.
Similar assays with HCT116 p53(-/-) cells reveal no significant differences with the parental
HCT116.
Treatment of HCT116 cells with 100nM LAQ824 leads to decrease the protein level of betacatenin
and to downregulate consequently its target genes, c-jun, c-myc and cyclin D1.
Similar effects are also observed when cells are treated with 0,5µM Trichostatin A and 5mM
Valproic acid. HDAC2, an indirect target of beta-catenin which is overexpressed in colon
cancer tissues, is downregulated by VPA but not by LAQ and TSA.
Our results demonstrate that LAQ824 inhibit cell proliferation and induces apoptosis in a
caspase-dependent and p53-independent manner and indicate that Wnt signaling could be
involved in the anti-tumor effects of LAQ824.
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